Obesity and type 2 diabetes are two of the major causes of morbidity and mortality in the Western world. Obese patients have a high incidence of type 2 diabetes and manifest both hyperinsulinemia and hyperleptinemia. Receptors for insulin and IGF-I and for leptin are expressed in the pancreatic islets, and recent reports have suggested that leptin can act through some components of the insulin-signaling cascade in different tissues. Although studies have examined the interactions between insulin and leptin in muscle and hepatocytes, the role(s) of these hormones in modulating islet function is not fully explored. We and others have shown that genetically engineered defects in insulin/IGF-I signaling, at the level of the beta-cell, can contribute to alterations in glucose homeostasis. Thus, mice with beta-cell specific knockouts of the insulin or IGF-1 receptors manifest defects in glucose-stimulated insulin secretion and develop glucose intolerance, but surprisingly do not show alterations in the growth and development of the beta-cell/islets. In contrast, IRS-2 knockouts show insulin resistance and beta-cell hypoplasia leading to early onset diabetes. On the other hand, leptin has been demonstrated to suppress insulin secretion both in vitro and in vivo in mice and humans and to promote beta-cell growth in insulinoma cells. The broad goals of this proposal are to identify the cellular mechanisms by which the proteins transmitting the insulin/IGF-I signal, interface with the leptin signaling pathway, in regulating insulin secretion, hormone biosynthesis and beta-cell proliferation, to understand the cross talk between two relatively novel signaling pathways in the islets, and to understand the cause(s) of (-cell failure in type 2 diabetes in the context of obesity. The specific aims of this proposal are to: 1) investigate the ability of leptin to activate proteins in the insulin/IGF-I signaling pathway in beta-cell lines and islets, 2) examine the effects of leptin on islet hormone secretion, islet metabolism and alterations in Ca++ flux in islets and 13-cell lines isolated from mice lacking the insulin or IGF-I receptors or IRS proteins, and 3) study the effects of leptin on beta-cell proliferation. My past experience in investigating the effects of leptin action in islet physiology and the experience I have gained in cellular signaling techniques by interacting with Dr. Ron Kahn's group, as I move to independence, provides me with a unique perspective to explore the interactions between the leptin and insulin/IGF-I signaling pathways in the islets. The additional funding for studies, during the last two years of the KO8 Award, will be useful to perform pilot experiments to obtain preliminary data to apply for a RO1 application and will allow the applicant to gain independence from the mentor's field.